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Breast Neoplasms

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Breast Diseases

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1500 mg lapatinib for 6 weeks followed by lapatinib plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant lapatinib.

4 mg/kg IV loading dose followed by 2 mg/kg IV weekly trastuzumab for 6 weeks followed by 2 mg/kg trastuzumab plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks).

1000 mg lapatinib plus 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly trastuzumab for 6 weeks, followed by 750 mg lapatinib plus 2 mg/kg IV weekly trastuzumab plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant lapatinib (1000 mg) in combination with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks).

Small molecule receptor tyrosine kinase inhibitor

Novartis Pharmaceuticals

This is a randomised, open label multicenter Phase III study comparing the efficacy of neoadjuvant lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant lapatinib and trastuzumab plus paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer.

Patients will be randomised to receive either: lapatinib 1500 mg daily, trastuzumab 4 mg/kg intravenous (IV) load followed by 2 mg/kg IV weekly, or lapatinib 1000 mg daily with trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for a total of 6 weeks. After this biological window, patients on monotherapy arms will continue on the same targeted therapy plus weekly paclitaxel 80 mg/m\^2 for a further 12 weeks, up to definitive surgery. In the combination arm, patients will receive lapatinib 750 mg daily in combination with trastuzumab 2 mg/kg IV plus weekly paclitaxel 80mg/m\^2 IV for a further 12 weeks, up to definitive surgery. After surgery, patients will receive three courses of adjuvant chemotherapy with 5-Fluorouracil Epirubicin Cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant setting for a further 34 weeks (in the combination arm, lapatinib dose will be 1000 mg daily in combination with trastuzumab). The planned total duration of the anti-HER2 therapy one year.

Primary objective is to evaluate and compare the rate of pathological complete response (pCR) at the time of surgery in patients with HER2/ErbB2 overexpressing or amplified operable breast cancer randomised to lapatinib followed by lapatinib plus paclitaxel versus trastuzumab followed by trastuzumab plus paclitaxel versus lapatinib in combination with trastuzumab followed by lapatinib, trastuzumab plus paclitaxel.

This was a parallel group, three-arm, randomized, multicenter, open-label phase III study. The study compared the efficacy and tolerability of neoadjuvant lapatinib and paclitaxel, versus trastuzumab and paclitaxel, versus the combination of lapatinib with trastuzumab and paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer. Subjects were randomized to receive lapatinib, trastuzumab or lapatinib plus trastuzumab for a total of 6 weeks. After this biological window, subjects continued on the same targeted therapy plus weekly paclitaxel for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). Paclitaxel could be initiated at Week 4 if there is evidence of progressive disease (PD) at that time. Within 6 weeks after surgery, subjects received 3 cycles of adjuvant 5-flourouracil, epirubicin and cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy).

After completing 52 weeks of (neo-)/adjuvant anti-HER2 therapy, subjects were scheduled to attend post-treatment follow-up every 3 months during the first year (months 12, 15, 18, 21, and 24), every 6months in Years 3 to 5 inclusive, and annually thereafter up to Year 10. Each subject was to be followed for 10 Years. All subjects were to be followed for EFS and OS up to 10 years from last subject randomized.

Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study

Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study: A Randomised, Multicenter Open-label Phase III Study of Neoadjuvant Lapatinib, Trastuzumab and Their Combination Plus Paclitaxel in Women With HER2/ErbB2 Positive Primary Breast Cancer

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Pathological complete response is defined as no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. Surgical breast and axillary node resection specimens were evaluated for pathologic tumor response according to National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines, which do not take into account the histological nodal status.

The number of participants with overall response (complete response and/or partial response) was evaluated using World Health Organization (WHO) criteria by clinical examination and by mammography and breast echography with bi-dimensional measurements at Week 6. As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.

The number of participants with overall response (complete response and/or partial response) was evaluated using WHO criteria by clinical examination and mammography and breast echography with bi-dimensional measurements at the time of surgery (Weeks 20 to 22). As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.

Participants were assessed for node-negative lymph nodes at the time of surgery. As per the pathological TNM (Tumor, Node, Metastases) classification (pTNM) of malignant tumors: pN, absence or presence and extent of regional lymph node metastasis. Node-negative (pN0) participants had no regional lymph node metastasis. Although not assessed in this measure, pT is the extent of primary tumor, and pM is the absence or presence of distant metastasis.

Participants were assessed for the type of surgery they underwent for breast cancer. Non-conservative surgery is defined as a radical or modified radical mastectomy. Conservative surgery is comprised of a lumpectomy, a quadrantectomy/segmentectomy, or a partial mastectomy. Participants who were not assessed as being candidates for non-conservative or conservative surgery were classified as non-operable.

Mean change from baseline in tumor in tumor size. Change from baseline in tumor size was defined as tumor size at Week 6/ surgery (Weeks 20 to 22) minus tumor size at baseline. The difference in treatment arms was estimated for Lapatinib 1500 mg versus Trastuzumab 2 mg/kg and for Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg versus Trastuzumab 2 mg/kg.

Participants with progressive disease at 4 week assessment that were permitted to commence treatment with paclitaxel.

Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.

Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.

The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis.

Clinical follow-up is the period during which the patient is monitored such that all recurrence or second primary malignancy (SPM) or contralateral breast cancer (CBC) events would be reported. Patients are considered in clinical follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death.

The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis.

For patients who had breast cancer surgery, EFS events are post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For patients who do not undergo breast cancer surgery, EFS events are death during clinical follow-up or non-completion of any neo-adjuvant investigational product due to disease progression or second primary malignancy or contralateral breast cancer.

The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis.

Patients are considered in survival follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death. For subjects with no death recorded in the database, time to death is censored.

The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Includes deaths due to any cause.

Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)

Biomarker levels of phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) were assessed in participants at baseline.

Biomarker levels of phosphate and tensin homolog deleted from chromosome 10 (PTEN) were assessed in participants at baseline.

Ratio (95% CI) of geometric means in p95 human epidermal growth factor receptor (p95HER2) expression in hormone-receptor (HR) positive patients with pathological complete response (pCR) vs no pCR

Circulating tumor cells (CTCs) are cells that have detached from a primary tumor and circulate in the bloodstream. In the adjuvant phase, after surgery all participants received 3 courses of adjuvant 5-fluorouracil, epirubicin and cyclophosphamide, followed by lapatinib 1500 mg or trastuzumab 2 mg/kg or lapatinib 1000/750 mg plus trastuzumab 2 mg/kg given prior to surgery in the neoadjuvant setting for an additional 34 weeks.

Breast International Group

SOLTI Breast Cancer Research Group

Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m\^2 IV) for an additional 12 weeks

Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg

Oral lapatinib (1500 milligrams \[mg\] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared \[mg/m\^2\]) intravenous (IV) for an additional 12 weeks

Lapatinib 1500 mg

Trastuzumab (4 mg/kilograms \[kg\] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m\^2 IV) for an additional 12 weeks

Trastuzumab 2 mg/kg

Total

Age, Continuous

Sex: Female, Male

American Indian or Alaska Native

Asian - Central/South

Asian - East

Asian - South East

Black or African American/African Heritage

White - Arabic/North African Heritage

White - Caucasian European Heritage

Missing

Race/Ethnicity, Customized

Well differentiated

Moderately differentiated

Poorly differentiated

Differentiation cannot be assessed

Histologic grade, also called differentiation, refers to how much the tumor cells resemble normal cells of the same tissue type.

Number of participants with tumor cells of the indicated histologic grade

N2 (including N2a and N2b)

N3 (including N3a, N3b, and N3c)

Clinical N stage is an evaluation/staging of LN status through physical examination. N0, no regional LN metastasis; N1, metastasis to movable ipsilateral axillary LNs (IALNs); N2a, metastasis in IALNs fixed to one another (matted) or the other structures; N2b, metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary LN metastasis; N3a, metastasis in ipsilateral infraclavicular LNs; N3b, metastasis in ipsilateral internal mammary LNs fixed and axillary LN; N3c, metastasis in ipsilateral subclavicar LNs; Nx, not assessed.

Number of participants with lymph nodes (LNs) of the indicated clinical N stage

Not applicable

Equivocal: Score of 2+

Positive: Score of 3+

Negative: Score of 0-1+

Non interpretable

An Immunohistochemistry (IHC) test gives a score of 0 to 3+, which indicates the amount of Human Epidermal Growth Factor (HER2) receptor proteins on the cancer cells in the sample tissue. A positive score (3+) indicates that HER2 receptor protein is present, a negative score (0-1+) indicates that no HER2 receptor protein is present, and an equivocal score (2+) indicates uncertainty and a result that is open for interpretation. Equivocal results require additional testing. "Not applicable" refers to the number of participants who did not have IHC testing done.

Number of participants with the indicated IHC results

Amplified

Not amplified

Not interpretable

The Fluorescent In Situ Hybridization (FISH) assay was used to determine the overexpression and/or amplification of HER2 in the invasive component of the primary tumor. Amplified indicates that the cell is overexpressing copies of the HER2 gene. Not amplified indicates that there is no overexpression of copies of the HER2 gene. "Not applicable" refers to the number of participants who did not have the FISH assay performed.

Number of participants with the indicated FISH results

Clinical Disclosure Office

Intent-to-Treat (ITT) Population: all participants randomized to treatment, except for those who withdrew their consent to use any of their data (permitted by law in certain countries) prior to receiving any study medication

Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery

Overall Response

No Change

Progressive Disease

Not Evaluated

Missing Data

Number of Participants With Overall Response at Week 6

Overall Response at the Time of Surgery

ITT Population. Participants with a lymph node status of pNX (i.e., regional lymph nodes cannot be assessed) were omitted from the analysis of node-negative participants.

Number of Participants With Negative Lymph Nodes at the Time of Surgery

Conservative

Non-conservative

Non-operable

Number of Participants With Actual Indicated Surgery

Week 6

Surgery (Weeks 20 to 22)

Mean Change From Baseline in Tumor Size at Week 6 and at Surgery

ITT Population. Participants who did not start any treatment were excluded from analysis.

Number of Participants Starting Paclitaxel Before Completing 6 Weeks of Treatment With Either Lapatinib or Trastuzumab

Event-free Survival (EFS) - Median Clinical Follow-up

Number of subjects with EFS events

Number of subjects censored - total

Number of subjects censored - Clinical follow-up ongoing

Number of subjects censored - Clinical follow-up ended - total

Number of subjects censored -Clinical follow-up ended - Completed study follow-up

Number of subjects censored - Clinical follow-up ended - Lost to follow-up

Number of subjects censored - Clinical follow-up ended - Withdrew (but consent for survival f/u)

Number of subjects censored - Clinical follow-up ended - Withdrew

Number of subjects censored - Other

Event-free Survival (EFS) - Events and Censoring

Overall Survival (OS) - Median Survival Follow-up

Number of deaths due to any cause

Number of subjects censored - Survival follow-up ongoing

Number of subjects censored - Survival follow-up ended - total

Number of subjects censored -Survival follow-up ended - Completed study follow-up

Number of subjects censored - Survival follow-up ended - Lost to follow-up

Number of subjects censored - Survival follow-up ended - Withdrew

Overall Survival (OS) - Deaths and Censoring

Overall - All subjects in the EFS landmark analysis

Subjects in the EFS landmark analysis in the lapatinib + trastuzumab arm

Subjects in the EFS landmark analysis in the lapatinib arm

Subjects in the EFS landmark analysis in the trastuzumab arm

Median clinical follow-up - all subjects in the EFS landmark analysis

Median clinical follow-up- EFS landmark analysis - lapatinib + trastuzumab arm (n=67,71,138)

Median clinical follow-up - subjects in the EFS landmark analysis - lapatinib arm (n=30,104,134)

Median clinical follow-up - subjects in the EFS landmark analysis - trastuzumab arm (n=39,99,138)

locoregional pathological Complete Response (pCR)

Pathological Complete Response (pCR)

no locoregional pathological Complete Response (pCR)

No Pathological Complete Response (pCR)

Overall

For EFS, the landmark population was the subset of the ITT population who have not had an EFS event within 30 weeks after randomization and were still in clinical follow-up.

Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Median Clinical Follow-up (EFS Landmark Population)

All subjects in the EFS landmark analysis with EFS events

Subjects in the EFS landmark analysis - lapatinib + trastuzumab arm with EFS events (n=67,71,138)

Subjects in the EFS landmark analysis in the lapatinib arm with EFS events (n=30,104,134)

Subjects in the EFS landmark analysis in the trastuzumab arm with EFS events (n=39,99,138)

Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of Participants With EFS Events (EFS Landmark Population)

Overall - All subjects in the OS landmark analysis

Subjects in the OS landmark analysis in the lapatinib + trastuzumab arm

Subjects in the OS landmark analysis in the lapatinib arm

Subjects in the OS landmark analysis in the trastuzumab arm

Median survival follow-up - All subjects in the OS landmark analysis

Median survival follow-up - OS landmark analysis in the lapatinib + trastuzumab arm (n=67,72,139)

Median survival follow-up - OS landmark analysis in the lapatinib (n=30,109,139)

Median survival follow-up - OS landmark analysis in the trastuzumab arm (n=40,102,142)

For OS, the landmark population was the subset of the ITT population who were alive and were followed up for overall survival 30 weeks after randomization.

Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Median Clinical Follow-up (OS Landmark Population)

All participants in the OS landmark analysis who died

Participants in the OS landmark analysis in the lapatinib + trastuzumab arm who died (n=67,72,139)

Participants in the OS landmark analysis in the lapatinib arm who died (n=30,109,139)

Participants in the OS landmark analysis in the trastuzumab arm who died (n=40,102,142)

Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Number of Participants Who Died (OS Landmark Population)

To Assess Safety Via a Comparison of the Three Treatment Arms - to Measure On-treatment Primary Cardiac Endpoints

Metabolic Response Rate (%) Determined by PET/CT at week 2

Metabolic Response Rate (%) Determined by PET/CT at week 6

Translational Data Set. Note that evaluable samples were not available for all participants.

Metabolic Response Rate Determined by Positron Emission Tomography/Computed Tomography (PET/CT)

Percentage of Participants With the Indicated Biomarker Expression - PIK3CA.

Biomarker: PTEN by Cell Signalling Technology - PTEN Normal (%)

Biomarker: PTEN by Cell Signalling Technology - PTEN Loss (%)

Percentage of Participants With the Indicated Biomarker Expression - PTEN.

Ratio (95% CI) of Geometric Means in p95HER2 Expression in HR Positive Patients With pCR vs no pCR

Percentage of Participants With Circulating Tumor Cells (CTC) in the Bloodstream

Total Deaths

On-Treatment Deaths (n=151,148,149)

On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, which was approximately 31 weeks. Deaths post treatment survival follow up were collected after the on treatment period, up to 10 years.

Safety population (for on-treatment deaths) and ITT (for total deaths)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study	NCT00553358	Neoplasms, Brea...	Lapatinib Trastuzumab Paclitaxel	18 Years -	Novartis
Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study	NCT00553358	Neoplasms, Brea...	Lapatinib Trastuzumab Paclitaxel	18 Years -	Novartis

Spots Global Cancer Trial Database for breast cancer positive for human epidermal growth factor receptor 2 (her2) her2 positive metastatic breast cancer